Cellular Senescence Contributes to Large Elastic Artery Stiffening and Endothelial Dysfunction With Aging: Amelioration With Senolytic Treatment

Abstract

BACKGROUND AND METHODS: To determine the role of cellular senescence and the senescence-associated secretory phenotype (SASP) in age-related aortic stiffening and endothelial dysfunction, we studied young (6–8 months) and old (27–29 months) p16-3MR mice, which allows for genetic-based clearance of senescent cells with ganciclovir (GCV). We also treated old C57BL/6 N mice with the senolytic ABT-263. RESULTS: In old mice, GCV reduced aortic stiffness assessed by aortic pulse wave velocity (pulse wave velocity, 477±10 versus 382±7 cm/s; P <0.05) to young levels (old GCV versus young vehicle; P =0.35); ABT-263 also reduced aortic pulse wave velocity in old mice (446±9 to 356±11 cm/s; P <0.05). Aortic adventitial collagen was reduced by GCV ( P <0.05) and ABT-263 ( P =0.12) in old mice. To show an effect of the circulating SASP, we demonstrated that plasma exposure from old-vehicle p16-3MR mice, but not from old- GCV mice, induced aortic stiffening assessed ex vivo (elastic modulus; P <0.05). Plasma proteomics implicated glycolysis in circulating SASP-mediated aortic stiffening. In old p16-3MR mice, GCV increased endothelial function assessed via peak carotid artery endothelium-dependent dilation (old ganciclovir, 94±1% versus old vehicle, 84±2%, P <0.05) to young levels (old GCV versus young vehicle, P =0.98), and endothelium-dependent dilation was higher in old C57BL/6 N mice treated with ABT-263 versus vehicle (96±1% versus 82±3%; P <0.05). Improvements in endothelial function were mediated by increased nitric oxide bioavailability ( P <0.05) and reduced oxidative stress ( P <0.05). Circulating SASP factors related to nitric oxide signaling were associated with higher nitric oxide–mediated endothelium-dependent dilation following senescent cell clearance. CONCLUSIONS: Cellular senescence and the SASP contribute to vascular aging, and senolytics hold promise for improving age-related vascular function.

Exercise to Prevent Accelerated Vascular Aging in People Living With HIV

“…[167][168][169][170][171] Cellular senescence is a multifactorial stress response that causes cell cycle arrest. 172 Senescent cells are stably viable and can influence neighboring cells by secreting proinflammatory cytokines and chemokines, angiogenic factors, metabolites, and growth factors (ie, senescence-associated secretory phenotype) that further contribute to inflammation, oxidative stress, and tissue dysfunction. 172,173 In the context of chronic HIV infection, it is thought that continual HIV antigen stimulation is associated with greater cell divisions, telomere erosion, and subsequently reduced proliferative capacity (ie, senescence) of T cells.…”

“…172 Senescent cells are stably viable and can influence neighboring cells by secreting proinflammatory cytokines and chemokines, angiogenic factors, metabolites, and growth factors (ie, senescence-associated secretory phenotype) that further contribute to inflammation, oxidative stress, and tissue dysfunction. 172,173 In the context of chronic HIV infection, it is thought that continual HIV antigen stimulation is associated with greater cell divisions, telomere erosion, and subsequently reduced proliferative capacity (ie, senescence) of T cells. 168 Emerging evidence indicates that senescent T cells and the accompanying senescence-associated secretory phenotype contribute to hypertension and vascular aging in people without HIV.…”

“…168 Emerging evidence indicates that senescent T cells and the accompanying senescence-associated secretory phenotype contribute to hypertension and vascular aging in people without HIV. [172][173][174][175][176] For example, the frequency of circulating senescent angiogenic CD4+ T cells, which are involved in endothelial regulation, is negatively related to FMD and systemic inflammation in people with hypertension. 177 Membrane microparticles shed from T cells can exacerbate endothelial dysfunction by reducing NO-mediated vasodilation via decreased endothelial nitric oxide synthase expression.…”

Intermittent supplementation with fisetin improves arterial function in old mice by decreasing cellular senescence

“…Leveraging genetic senolysis models in combination with senolytic agents is considered the reference standard for assessing the causal impact of cellular senescence on physiological function (Clayton et al, 2023;Demaria et al, 2014Demaria et al, , 2017. Thus, to selectively clear senescent cells, we incubated carotid arteries isolated from old vehicle-and fisetin-supplemented p16-3MR mice with 5 μM GCV and assessed EDD prior to and after the incubation period.…”

“…Nonetheless, senescent endothelial cells highly express p16 INK4A and, as such, the p16-3MR mouse model is a highly relevant model to study the role of cellular senescence in arterial aging (Clayton et al, 2023).…”